The overall goals of Project 3 are to determine the complex biochemical and pathophysiological bases for the altered interactions of artemisinins with erythrocytic constituents in the alpha- and beta-thalassemias, Hb H and Hb H/CS disease, and the Hb E syndromes. Artemisinin is a very potent anti-malarial drug derived from a Chinese herb, Artemisia annua Linn. It's structure contains a endoperoxide bridge, which is believed to exert damages to the parasite. Artemisinin and its derivatives are a very effective against chloroquine-resistant parasites. They have been used extensively in the treatment of cerebral and complicated malaria with no report of serious side effects nor resistance in the field. In our preliminary work, we have found that artemisinin accelerates parasite usefulness of this anti-malarial agent, it is important to understand factor that might modify the efficacy of this drug in future. To improve our understanding of the biochemical and pathophysiological factors responsible for these alterations in anti-malarial activity by the thalassemias and hemoglobinopathies, the specific aims of the component studies of Project 3 are: Study 1: to determine the factors responsible for the binding and inactivation of artemisinin by thalassemic erythrocytes; Study 2: to examine the role of host genetic factors in the development of resistance to artemisinin; Study 3: to determine the mechanisms responsible for the enhanced anti- malarial activity of artemisinin in Hb E trait erythrocytes.. Study 4: to examine the effects of artemisinin on malaria parasite gene expression The outcome of these studies can aid not only in designing proper drug regimens for malaria-infected patients with different genetic backgrounds, but can also help in preventing the emergence of artemisinin resistance.